Theranostics 2020; 10(24):10925-10939. doi:10.7150/thno.49425

Research Paper

Targeting positive feedback between BASP1 and EGFR as a therapeutic strategy for lung cancer progression

Ching-Chan Lin1,8, Yu-Kai Huang2, Chia-Fong Cho10, Yu-Sen Lin1,9, Chia-Chien Lo10, Ting-Ting Kuo10, Guan-Chin Tseng11, Wei-Chung Cheng2,6,7, Wei-Chao Chang10, Tzu-Hung Hsiao14, Liang-Chuan Lai15, Jin-Yuan Shih16,17, Yu-Huei Liu5,12, K.S. Clifford Chao13, Jennifer L. Hsu18, Pei-Chih Lee2, Xian Sun18,19, Mien-Chie Hung2,10, Yuh-Pyng Sher1,2,3,4,10✉

1. Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.
2. Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan.
3. Chinese Medicine Research Center, China Medical University, Taichung 404, Taiwan.
4. Research Center for Chinese Herbal Medicine, China Medical University, Taichung 404, Taiwan.
5. Graduate Institute of Integrated Medicine, China Medical University, Taichung 404, Taiwan.
6. Research Center for Tumor Medical Science, China Medical University, Taichung 404, Taiwan.
7. Drug Development Center, China Medical University, Taichung 404, Taiwan.
8. Division of Hematology and Oncology, China Medical University Hospital, Taichung 404, Taiwan.
9. Division of Thoracic Surgery, China Medical University Hospital, Taichung 404, Taiwan.
10. Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan.
11. Department of Anatomic Pathology, Nantou Hospital of the Ministry of Health and Welfare, Nantou 540, Taiwan.
12. Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung 404, Taiwan.
13. Cancer Center, China Medical University Hospital, Taichung 404, Taiwan.
14. Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.
15. Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
16. Graduate Institute of Clinical Medicine, National Taiwan University, Taipei 106, Taiwan.
17. Department of Internal Medicine, National Taiwan University Hospital, Taipei 106, Taiwan.
18. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
19. Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.

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Citation:
Lin CC, Huang YK, Cho CF, Lin YS, Lo CC, Kuo TT, Tseng GC, Cheng WC, Chang WC, Hsiao TH, Lai LC, Shih JY, Liu YH, Chao KSC, Hsu JL, Lee PC, Sun X, Hung MC, Sher YP. Targeting positive feedback between BASP1 and EGFR as a therapeutic strategy for lung cancer progression. Theranostics 2020; 10(24):10925-10939. doi:10.7150/thno.49425. Available from http://www.thno.org/v10p10925.htm

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Abstract

Rationale: Brain metastasis in patients with lung cancer is life-threatening. However, the molecular mechanism for this catastrophic disease remains elusive, and few druggable targets are available. Therefore, this study aimed to identify and characterize proteins that could be used as therapeutic targets.

Methods: Proteomic analyses were conducted to identify differentially expressed membrane proteins between brain metastatic lung cancer cells and primary lung cancer cells. A neuronal growth-associated protein, brain acid soluble protein 1 (BASP1), was chosen for further investigation. The clinical relevance of BASP1 in lung adenocarcinoma was first assessed. Tyrosine kinase activity assays and in vitro and in vivo functional assays were conducted to explore the oncogenic mechanisms of BASP1.

Results: The protein levels of BASP1 were positively associated with tumor progression and poor prognosis in patients with lung adenocarcinoma. Membrane-bound BASP1 increased EGFR signaling and stabilized EGFR proteins by facilitating their escape from the ubiquitin-proteasome pathway. Reciprocally, activation of EGFR recruited more BASP1 to the plasma membrane, generating a positive feedback loop between BASP1 and EGFR. Moreover, the synergistic therapeutic effects of EGFR tyrosine kinase inhibitor and arsenic trioxide led to a reduction in the level of BASP1 protein observed in lung cancer cells with acquired resistance to EGFR inhibitors.

Conclusions: The reciprocal interaction between BASP1 and EGFR facilitates EGFR signaling in brain metastatic lung cancer. Targeting the newly identified BASP1-EGFR interaction could open new venues for lung cancer treatment.

Keywords: lung adenocarcinoma, BASP1, arsenic trioxide, EGFR-TKI acquired resistance, combination therapy